Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice

Abstract

Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC. Galeterone (gal), a multi-target, agent in phase III clinical development for prostate cancer has also shown effects on the aforementioned pathways. We show for the first time, that gal/analogs (VNPT55, VNPP414 and VNPP433-3β) profoundly inhibited cell viability of gemcitabine-naive/resistance PDAC cell lines and strongly synergized with gemcitabine in gemcitabine-resistant PDAC cells. In addition, to inducing G1 cell cycle arrest, gal/analogs induced caspase 3-mediated cell-death of PDAC cells. Gal/analogs caused profound downregulation of Mnk1/2, peIF4E and NF-κB (p-p65), metastatic inducing factors (N-cadherin, MMP-1/-2/-9, Slug, Snail and CXCR4) and putative stem cell factors, (β-Catenin, Nanog, BMI-1 and Oct-4). Gal/analog also depleted EZH2 and upregulated E-Cadherin. These effects resulted in significant inhibition of PDAC cell migration, invasion and proliferation. Importantly, we also observed strong MiaPaca-2 tumor xenograft growth inhibition (61% to 92%). Collectively, these promising findings strongly support further development of gal/analogs as novel therapeutics for PDAC.

Targeting of protein translation as a new treatment paradigm for prostate cancer

“…MNK degraders comprise of novel retinamides, galeterone (gal), and gal analogs (e.g., VNPT55) which have shown promise in inhibiting eIF4E activation and tumor growth in prostate, breast and pancreatic cancers [33,64–67]. MNK inhibitors, including CGP052088, CGP57380, cercosporamide, and 5-(2-(phenyloamino)pyrymidin-4-yl)thiazole-2(3H)-one derivatives, have also been well studied [58].…”

“…Gal and its analogs (VNPT55, VNPP414 and VNPP433-3β) have also been recently found to downregulate MNK1/2 and peIF4E with associated induction of G1 cell cycle arrest, caspase 3-mediated cell-death, and inhibition of cell migration/invasion in gemcitabine-sensitive and –resistant pancreatic ductal adenocarcinoma (PDAC) cells. Further, these agents strongly inhibit tumor growth in MiaPaca-2 tumor xenografts (61% to 92%) by depleting MNK1/2 and peIF4E [67]. …”

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

“…Kumar et al also showed that 5-fluorouracil-chemoresistant PDAC cells, which have undergone EMT and have increased ZEB1 levels, are sensitive to MNK inhibition and have fewer cancer stem cells after CGP57380 treatment [70]. Kwegyr-Afful et al demonstrated that galeterone and its analogs (VNPT55, VNPP414, and VNPP433-3β) synergize with gemcitabine and inhibit PDAC migration, invasion and proliferation of gemcitabine-naïve and resistant PDAC cells through downregulation of MNK1/2 and suppress tumor growth of PDAC xenografts in mice [91] (Figure 8). Based on these results, galeterone is currently in clinical trials (phase II) in advanced PDAC alone and in combination with gemcitabine ( Table 2).…”

Synthesis, Characterisation and Cytotoxicity of Gold Nanowires for Ultra-Sensitive Biosensor Development

“…Early identi cation of disease blood protein signatures, is becoming the most promising strategy for effective cancer prevention. Nevertheless, some protein biomarkers, such as those secreted by cell death in tumours at a very early growth period, are produced only at ultra-low concentrations [7][8][9][10]. Engineered nanomaterials-based biosensors with high sensitivity levels have been the focus of improved biomarker detection technology [11][12][13][14].…”